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NAD AND Ampk

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https://www.readbyqxmd.com/read/29156703/preclinical-efficacy-of-the-novel-competitive-nampt-inhibitor-stf-118804-in-pancreatic-cancer
#1
Jair Machado Espindola-Netto, Claudia C S Chini, Mariana Tarragó, Enfeng Wang, Shamit Dutta, Krishnendu Pal, Debabrata Mukhopadhyay, Mauro Sola-Penna, Eduardo N Chini
NAD salvage is one of the pathways used to generate NAD in mammals. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in this pathway, uses nicotinamide (NAM) to generate nicotinamide mononucleotide (NMN). NMN is one of the main precursors of NAD synthesis in cells. Our previous study showed the importance of NAMPT in maintaining NAD levels in pancreatic ductal adenocarcinoma cells (PDAC), and that the NAMPT inhibitor FK866 decreased pancreatic cancer growth. We now tested the effect of STF-118804, a new highly specific NAMPT inhibitor, in models of pancreatic ductal adenocarcinoma...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29106036/inhibition-of-mitochondrial-complex-i-improves-glucose-metabolism-independently-of-ampk-activation
#2
Wo-Lin Hou, Jun Yin, Miriayi Alimujiang, Xue-Ying Yu, Li-Gen Ai, Yu-Qian Bao, Fang Liu, Wei-Ping Jia
Accumulating evidences showed metformin and berberine, well-known glucose-lowering agents, were able to inhibit mitochondrial electron transport chain at complex I. In this study, we aimed to explore the antihyperglycaemic effect of complex I inhibition. Rotenone, amobarbital and gene silence of NDUFA13 were used to inhibit complex I. Intraperitoneal glucose tolerance test and insulin tolerance test were performed in db/db mice. Lactate release and glucose consumption were measured to investigate glucose metabolism in HepG2 hepatocytes and C2C12 myotubes...
November 6, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/29091865/the-role-of-sirt1-in-diabetic-retinopathy
#3
REVIEW
Hedyieh Karbasforooshan, Gholamreza Karimi
The prevalence of diabetes mellitus (DM), has been increasing worldwide. Diabetic retinopathy (DR) is the most common microvascular complication in diabetes. It is a multifactorial disease that occurs primarily through the long-term detrimental effects of hyperglycemia. The pathogenesis of DR is complex, including inflammation, oxidative stress and advanced glycation end products (AGES). SIRT1 is a nicotinamide adenosine dinucleotide (NAD+)-dependent deacetylase that removes acetyl groups from proteins which can be implicated in DR...
October 26, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29089150/hemin-reduces-hmgb1-release-by-uvb-in-an-ampk-ho-1-dependent-pathway-in-human-keratinocytes-hacat-cells
#4
Eun Jung Park, Young Min Kim, Ki Churl Chang
BACKGROUND AND AIMS: High mobility group box 1 (HMGB1) plays an important role as a pro-inflammatory cytokine that regulates inflammation in various diseases. We hypothesized that hemin might reduce HMGB1 release through the induction of HO-1 in UVB-induced HaCaTs. METHODS: The effects of hemin on the release of HMGB1 in UVB exposure were evaluated. The mechanisms were investigated using various signal inhibitors and small interfering RNA techniques. RESULTS: Treatment with hemin inhibited reactive oxygen species (ROS) in UVB-induced HaCaTs in a dose-dependent manner...
October 28, 2017: Archives of Medical Research
https://www.readbyqxmd.com/read/29080400/aging-and-stem-cell-therapy-ampk-as-an-applicable-pharmacological-target-for-rejuvenation-of-aged-stem-cells-and-achieving-higher-efficacy-in-stem-cell-therapy
#5
REVIEW
Mohammadhossein Khorraminejad-Shirazi, Mohammad Farahmandnia, Bahareh Kardeh, Alireza Estedlal, Sina Kardeh, Ahmad Monabati
In recent years, tissue regeneration has become a promising field for developing stem cell-based transplantation therapies for human patients. Adult stem cells are affected by the same aging mechanisms that involve somatic cells. One of the mechanisms involved in cellular aging is hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and disruption of 5' adenosine monophosphate-activated protein kinase (AMPK). Aging of stem cells results in their impaired regenerative capacity and depletion of stem cell pools in adult tissue, which results in lower efficacy of stem cell therapy...
October 19, 2017: Hematology/oncology and Stem Cell Therapy
https://www.readbyqxmd.com/read/29074724/conversion-of-prps-hexamer-to-monomer-by-ampk-mediated-phosphorylation-inhibits-nucleotide-synthesis-in-response-to-energy-stress
#6
Xu Qian, Xinjian Li, Lin Tan, Jong-Ho Lee, Yan Xia, Qingsong Cai, Yanhua Zheng, Hongxia Wang, Philip L Lorenzi, Zhimin Lu
Tumors override energy stress to grow. However, how nucleotide synthesis is regulated under energy stress is unclear. We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase (PRPS) 1 S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production. Knock-in of non-phosphorylatable PRPS1/2 mutants, which have uninhibited activity, in brain tumor cells under energy stress exhausts cellular ATP and NADPH and increases ROS levels, thereby promoting cell apoptosis...
October 26, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28982598/methyleugenol-protects-against-t-bhp-triggered-oxidative-injury-by-induction-of-nrf2-dependent-on-ampk-gsk3%C3%AE-and-erk-activation
#7
Junfeng Zhou, Xiaoyuan Ma, Yan Cui, Yang Song, Lei Yao, Yuanyuan Liu, Shanshan Li
Methyleugenol (Mlg), a natural ingredient of many herbs and used as a flavoring substance in dietary products, inhibits inflammation and oxidative stress. The aim of the study is to explore the antioxidative potential of Mlg against tert-butyl hydroperoxide (t-BHP)-triggered oxidative injury and the involvement of antioxidative mechanisms. Our findings indicated that Mlg exposure significantly alleviated t-BHP-stimulated cytotoxicity, suppressed reactive oxygen species (ROS) generation, and increased superoxide dismutase (SOD) and glutathione (GSH) levels, which were related to the induction of the glutamate-cysteine ligase catalytic/modifier (GCLC/GCLM) subunit, heme oxygenase-1 (HO-1), and NAD (P) H: quinone oxidoreductase (NQO1) largely dependent upon upregulating the nuclear factor-erythroid 2-related factor 2 (Nrf2) induction, inhibiting the Keap1 protein expression, and heightening the antioxidant response element (ARE) activity...
September 19, 2017: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/28973994/silibinin-restores-nad%C3%A2-%C2%BA-levels-and-induces-the-sirt1-ampk-pathway-in-non-alcoholic-fatty-liver
#8
Federico Salomone, Ignazio Barbagallo, Justyna Godos, Vincenzo Lembo, Walter Currenti, Diana Cinà, Roberto Avola, Nicolantonio D'Orazio, Filomena Morisco, Fabio Galvano, Giovanni Li Volti
Nicotinamide adenine dinucleotide (NAD⁺) homeostasis is emerging as a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and is tightly linked to the SIRT1/5'-AMP-activated protein kinase (AMPK) pathway. Silibinin, the main component of silymarin, has been proposed as a nutraceutical for the treatment of NAFLD. In this study, we aimed to identify whether silibinin may influence the NAD⁺/SIRT1 axis. To this end, C57BL/6 mice were fed a high fat diet (HFD) for 16 weeks, and were treated with silibinin or vehicle during the last 8 weeks...
September 30, 2017: Nutrients
https://www.readbyqxmd.com/read/28970491/rev1-contributes-to-proper-mitochondrial-function-via-the-parp-nad-sirt1-pgc1%C3%AE-axis
#9
Nima Borhan Fakouri, Jon Ambæk Durhuus, Christine Elisabeth Regnell, Maria Angleys, Claus Desler, Mahdi Hasan- Olive, Ana Martín-Pardillos, Anastasia Tsaalbi-Shtylik, Kirsten Thomsen, Martin Lauritzen, Vilhelm A Bohr, Niels de Wind, Linda Hildegard Bergersen, Lene Juel Rasmussen
Nucleic acids, which constitute the genetic material of all organisms, are continuously exposed to endogenous and exogenous damaging agents, representing a significant challenge to genome stability and genome integrity over the life of a cell or organism. Unrepaired DNA lesions, such as single- and double-stranded DNA breaks (SSBs and DSBs), and single-stranded gaps can block progression of the DNA replication fork, causing replicative stress and/or cell cycle arrest. However, translesion synthesis (TLS) DNA polymerases, such as Rev1, have the ability to bypass some DNA lesions, which can circumvent the process leading to replication fork arrest and minimize replicative stress...
October 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28756945/sirt1-functions-as-a-negative-regulator-of-eukaryotic-poly-a-rna-transport
#10
Peipei Shan, Guangjian Fan, Lianhui Sun, Jinqin Liu, Weifang Wang, Chen Hu, Xiaohong Zhang, Qiwei Zhai, Xiaoyu Song, Liu Cao, Yongping Cui, Shengping Zhang, Chuangui Wang
Most eukaryotic mRNAs are polyadenylated in the nucleus, and the poly(A)-tail is required for efficient mRNA export and translation. However, mechanisms governing mRNA transport remain unclear. Here, we report that the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase SIRT1 acts as an energy sensor and negatively regulates poly(A)RNA transport via deacetylating a poly(A)-binding protein, PABP1. Upon energy starvation, SIRT1 interacts with and deacetylates PABP1 and deactivates its poly(A)RNA binding, leading to nuclear accumulation of PABP1 and poly(A)RNA and thus facilitating eukaryotic cells to attenuate protein synthesis and energy consumption to adapt to energy stress...
August 7, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28751004/polyphenols-activate-energy-sensing-network-in-insulin-resistant-models
#11
Radika Mutlur Krishnamoorthy, Anuradha Carani Venkatraman
Unhealthy diet deficient in fruits and vegetables but rich in calories is considered to be one factor responsible for the increased prevalence of insulin resistance and type 2 diabetes (T2D). The consumption of fast foods and soft drinks increases fructose consumption per se and this is of major concern since prolonged fructose intake induces insulin resistance and thereby T2D. The energy homeostasis is regulated by a network consisting of "fuel gauze" called AMP-activated protein kinase (AMPK), the NAD(+) dependent type III deacetylase (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) which is disrupted in T2D...
September 25, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28736552/asiatic-acid-exhibits-anti-inflammatory-and-antioxidant-activities-against-lipopolysaccharide-and-d-galactosamine-induced-fulminant-hepatic-failure
#12
Hongming Lv, Zhimin Qi, Sisi Wang, Haihua Feng, Xuming Deng, Xinxin Ci
Inflammation and oxidative stress are essential for the pathogenesis of fulminant hepatic failure (FHF). Asiatic acid (AA), which is a pentacyclic triterpene that widely occurs in various vegetables and fruits, has been reported to possess antioxidant and anti-inflammatory properties. In this study, we investigated the protective effects of AA against lipopolysaccharide (LPS) and d-galactosamine (GalN)-induced FHF and the underlying molecular mechanisms. Our findings suggested that AA treatment effectively protected against LPS/d-GalN-induced FHF by lessening the lethality; decreasing the alanine transaminase and aspartate aminotransferase levels, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α production, malondialdehyde formation, myeloperoxidase level and reactive oxygen species generation (i...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28733523/preclinical-efficacy-of-the-novel-competitive-nampt-inhibitor-stf-118804-in-pancreatic-cancer
#13
Jair Machado Espindola-Netto, Claudia C S Chini, Mariana Tarragó, Enfeng Wang, Shamit Dutta, Krishnendu Pal, Debabrata Mukhopadhyay, Mauro Sola-Penna, Eduardo N Chini
NAD salvage is one of the pathways used to generate NAD in mammals. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in this pathway, uses nicotinamide (NAM) to generate nicotinamide mononucleotide (NMN). NMN is one of the main precursors of NAD synthesis in cells. Our previous study showed the importance of NAMPT in maintaining NAD levels in pancreatic ductal adenocarcinoma cells (PDAC), and that the NAMPT inhibitor FK866 decreased pancreatic cancer growth. We now tested the effect of STF-118804, a new highly specific NAMPT inhibitor, in models of pancreatic ductal adenocarcinoma...
June 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28708087/resveratrol-induced-amp-activated-protein-kinase-activation-is-cell-type-dependent-lessons-from-basic-research-for-clinical-application
#14
Fan Lan, Karen A Weikel, Jose M Cacicedo, Yasuo Ido
Despite the promising effects of resveratrol, its efficacy in the clinic remains controversial. We were the first group to report that the SIRT1 activator resveratrol activates AMP-activated protein kinase (AMPK) (Diabetes 2005; 54: A383), and we think that the variability of this cascade may be responsible for the inconsistency of resveratrol's effects. Our current studies suggest that the effect of SIRT1 activators such as resveratrol may not be solely through activation of SIRT1, but also through an integrated effect of SIRT1-liver kinase B1 (LKB1)-AMPK...
July 14, 2017: Nutrients
https://www.readbyqxmd.com/read/28587104/c1q-tnf-related-protein-9-ameliorates-ox-ldl-induced-endothelial-dysfunction-via-pgc-1%C3%AE-ampk-mediated-antioxidant-enzyme-induction
#15
Haijian Sun, Xuexue Zhu, Yuetao Zhou, Weiwei Cai, Liying Qiu
Oxidized low-density lipoprotein (ox-LDL) accumulation is one of the critical determinants in endothelial dysfunction in many cardiovascular diseases such as atherosclerosis. C1q/TNF-related protein 9 (CTRP9) is identified to be an adipocytokine with cardioprotective properties. However, the potential roles of CTRP9 in endothelial function remain largely elusive. In the present study, the effects of CTRP9 on the proliferation, apoptosis, migration, angiogenesis, nitric oxide (NO) production and oxidative stress in human umbilical vein endothelial cells (HUVECs) exposed to ox-LDL were investigated...
May 26, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28551846/ampk-and-sirt1-activation-contribute-to-inhibition-of-neuroinflammation-by-thymoquinone-in-bv2-microglia
#16
Ravikanth Velagapudi, Abdelmeneim El-Bakoush, Izabela Lepiarz, Folashade Ogunrinade, Olumayokun A Olajide
Thymoquinone is a known inhibitor of neuroinflammation. However, the mechanism(s) involved in its action remain largely unknown. In this study, we investigated the roles of cellular reactive oxygen species (ROS), 5' AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) in the anti-neuroinflammatory activity of thymoquinone. We investigated effects of the compound on ROS generation in LPS-activated microglia using the fluorescent 2',7'-dichlorofluorescin diacetate (DCFDA)-cellular ROS detection. Immunoblotting was used to detect protein levels of p40(phox), gp91(phox), AMPK, LKB1 and SIRT1...
May 27, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28533928/leucine-nicotinic-acid-synergy-stimulates-ampk-sirt1-signaling-and-regulates-lipid-metabolism-and-lifespan-in-caenorhabditis-elegans-and-hyperlipidemia-and-atherosclerosis-in-mice
#17
Antje Bruckbauer, Jheelam Banerjee, Quiang Cao, Xin Cui, Jia Jing, Lin Zha, Fenfen Li, Bingzhong Xue, Hang Shi, Michael B Zemel
BACKGROUND/AIMS: Nicotinic acid (NA), a lipid-lowering drug, serves as a source of NAD(+), the cofactor for Sirt1. Leucine (Leu) stimulates the AMPK/Sirt1 axis and amplifies the effects of other AMPK/Sirt1 activating compounds. Therefore, we tested the interactive effects of leucine and low dose NA on AMPK/Sirt1 signaling and downstream effects of lipid metabolism in cell culture, C. elegans and mice. METHODS: LDL-receptor knockout mice were fed an atherogenic Western diet supplemented with leucine (24 g/kg diet) and sub-therapeutic NA combinations (50 mg/kg diet and 250 mg/kg diet) or low therapeutic NA (1000 mg/kg diet) for 8 weeks to evaluate markers of hyperlipidemia and atherosclerosis...
2017: American Journal of Cardiovascular Disease
https://www.readbyqxmd.com/read/28528294/isoliquiritigenin-reduces-oxidative-damage-and-alleviates-mitochondrial-impairment-by-sirt1-activation-in-experimental-diabetic-neuropathy
#18
Veera Ganesh Yerra, Anil Kumar Kalvala, Ashutosh Kumar
Sirtuin (SIRT1) inactivation underlies the pathogenesis of insulin resistance and hyperglycaemia-associated vascular complications, but its role in diabetic neuropathy (DN) has not been yet explored. We have evaluated hyperglycaemia-induced alteration of SIRT1 signalling and the effect of isoliquiritigenin (ILQ) on SIRT1-directed AMP kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) signalling in peripheral nerves of streptozotocin (STZ) (55 mg/kg, ip)-induced diabetic rats and in high glucose (30 mM)-exposed neuro2a (N2A) cells...
May 11, 2017: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/28521876/renoprotective-effect-of-a-novel-selective-ppar%C3%AE-modulator-k-877-in-db-db-mice-a-role-of-diacylglycerol-protein-kinase-c-nad-p-h-oxidase-pathway
#19
Toshinobu Maki, Yasutaka Maeda, Noriyuki Sonoda, Hiroaki Makimura, Shinichiro Kimura, Sayaka Maeno, Ryoichi Takayanagi, Toyoshi Inoguchi
OBJECTIVE: Several clinical studies have shown the beneficial effects of peroxisome proliferator-activated receptor α (PPARα) agonists on diabetic nephropathy. However, the molecular mechanism is not fully understood. Here we show that K-877, a novel selective PPARα modulator, ameliorates nephropathy in db/db mice via inhibition of renal lipid content and oxidative stress. METHODS AND RESULTS: K-877 (0.5mg/kg/day) was administered to db/db mice for 2 or 12weeks...
June 2017: Metabolism: Clinical and Experimental
https://www.readbyqxmd.com/read/28509385/molecular-events-leading-to-death-of-leishmania-donovani-under-spermidine-starvation-after-hypericin-treatment
#20
Shalini Singh, Ekta Kumari, Ruchika Bhardwaj, Ritesh Kumar, Vikash Kumar Dubey
We have previously reported that the hypericin treatment caused spermidine starvation and death of Leishmania parasite. Here, we report different molecular events under spermidine starvation and potential role of spermidine in processes other than redox homeostasis of the parasite. We have analyzed changes in expression of several genes by using quantitative gene expression analysis. Further, these changes at molecular level were also confirmed by using biochemical and cellular studies. Altered expression of several genes involved in redox metabolism, hypusine modification of eIF5A, DNA repair pathway and autophagy was observed...
November 2017: Chemical Biology & Drug Design
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